The objective of this Core is to provide computational, bioinformatics and high throughput screening support for all three Projects. Computational support will include continued computer-aided design of new and/or improved inhibitors against SARS-CoV SCLpro and QSAR analysis of SCLpro inhibitor structures and activities to provide guidance in synthetic design (Project 3). Bioinformatics development of theoretical models for the 3-D structure of PLpro will be used as an initial foundation for PLpro structure-function studies (Project 1), for enzymatic mechanistic studies (Project 2) and for in silico screening of large chemical libraries for potential lead compounds (Projects). High throughput experimental screening will be used for initial lead discovery of PLpro inhibitors for Project 3; high throughput assays will be used for analysis of enzymatic mechanisms in Project 2. Bioinformatic analysis and modeling of protein substrate and protein-inhibitor interactions will be used to suggest particular mutations for hypothesis testing for enzymatic activity and mechanisms (Projects 1 and 2), and to predict inhibitor designs that will be least subject to mutational 'evasion'. This Core will thus provide centralized computational and high throughput assay screening for all three Projects.